Osteoarthritis is a highly prevalent, progressively disabling musculoskeletal disease characterized by degeneration of articular cartilage. Advanced stages of the disease result in functional disabilities ranging from mild to incapacitating. Currently, there are no disease-modifying agents for OA; one significant barrier to the development of such agents is the difficulty of early diagnosis and of assessment of subtle responses of cartilage to therapeutic interventions. Accordingly, we have identified molecular signatures associated with degenerative collagen in osteoarthritic human cartilage by an infrared fiber optic probe (IF(c)P), and now propose to extend this methodology to the actual clinical setting, where we envision the IFOP as an arthroscopic diagnostic tool to evaluate the chondral surface in joint diseases. This will be accomplished by correlation of infrared measures with standard MR Imaging outcomes, in conjunction with development of chemometric methods (statistically based pattern-recognition methods used to identify or classify materials based on their spectral characteristics) to automate analyses. Our first goal will be to use the IFOP to identify early-stage, pre-macroscopic degenerative surface cartilage in a rabbit model of OA by evaluation of collagen degradation and proteoglycan. The second goal will be to develop a chemometric method of cartilage classification based on IFOP spectra obtained from the cartilage surface of a rabbit model of OA, and from spectra from various stages of human OA tissue. Finally, our last goal builds on the foregoing work to apply IFOP analysis to the clinical setting by assessment of in vivo articular cartilage during knee arthroplasties prior to harvesting of tissues. This wil firmly lay the groundwork for the final clinical arthroscopic application of IFOP analysis of cartilage evaluation by permitting the establishment of optimal experimental parameters for IFOP analysis, such as sampling time and reproducibility of in vivo spectra. Thus, taken together, the proposed research program represents a coordinated bench-to-bedside analysis of molecular alterations in degraded cartilage by infrared spectroscopy. Currently, there are no non-destructive methods available for detection and classification of subtle molecular changes in cartilage integrity; therefore, IFOP analysis may play a truly central role in the exceedingly important emergent field of OA therapeutics by offering this capability.